The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

A highly practical method for the enantioselective allylation of ketone-derived benzoylhydrazones has been developed. The previously reported strained silacycle reagent 1 reacts with a wide variety of benzoylhydrazones to give the hydrazide products with good to excellent enantioselectivity (84-97% ee). A mechanism in which the acylhydrazone becomes caovalently attached to the silane has been established.

Hair count results show a modest and sustained improvement in hair growth with daily use of a 1% pyrithione zinc shampoo over a 26-week treatment period.

The enantioselective Friedel-Crafts reaction of electron-rich arenes and heteroarenes with the benzoylhydrazone of isopropyl glyoxylate mediated by a simple chiral silane Lewis acid is described. The reactions are highly practical, as demonstrated by a larger scale (5 g of the hydrazone) reaction in which the recovery of the pseudoephedrine in 99% yield was achieved. A simple model is advanced to explain the observed enantioselectivity.

The improved efficacy obtained with the combination therapy was accompanied by a tolerability profile similar to that of benzoyl peroxide alone, making this new combination product an alternative antimicrobial therapy for acne vulgaris.